Method for stimulating weight loss and/or for lowering triglycerides in patients

ABSTRACT

Administration of a therapeutically effective amount of 3,5-diiodothyropropionic acid stimulates weight loss in patients, lowers triglyceride levels and reduces risk of death or progression of coronary heart disease in patients with metabolic syndrome.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of co-pending applicationSer. No. 10/818,541, filed Apr. 5, 2004, which is, in turn acontinuation-in-part of U.S. application Ser. No. 10/368,755, filed Feb.18, 2003, now U.S. Pat. No. 6,716,877 issued Apr. 6, 2004, which is, inturn a continuation-in-part of U.S. application Ser. No. 09/774,994,filed Jan. 31, 2001, now U.S. Pat. No. 6,534,676, issued Mar. 18, 2003.

BACKGROUND OF THE INVENTION AND DISCUSSION OF THE PRIOR ART

Researchers at the Centers for Disease Control and Prevention (CDC)estimated that as many as 47 million Americans may exhibit a cluster ofmedical conditions (a “metabolic syndrome”) characterized by abdominalobesity, hypertriglyceridemia, low high-density lipoprotein (HDL)cholesterol, high blood pressure, and elevated fasting blood glucose[1]. Having three or more traits of metabolic syndrome significantlyincreases the risk of dying from coronary heart disease orcardiovascular disease. It has also been reported that patients witheven one or two metabolic syndrome traits, or those with metabolicsyndrome but without diabetes also were at increased risk for death fromcoronary heart disease or cardiovascular disease.

Obesity and atherosclerosis have a major impact on morbidity andmortality in the United States and many other countries. Elevatedcholesterol, particularly low-density lipoprotein (LDL) cholesterol, isa major risk factor for atherosclerosis. Thyroid hormone replacement inhypothyroid individuals reduces total cholesterol and LDL-cholesterol[2-4]. An excess of thyroid hormone in thyrotoxicosis causes weightloss. The weight loss consists not only of fat but also muscle mass andeven myopathy can be observed [5].

The ability of thyroid hormone to lower cholesterol when given tohypothyroid individuals prompted efforts to design analogs that takeadvantage of these properties in the treatment of hypercholesterolemia.This action is the result of an accelerated LDL-cholesterol clearancerate [6-8]. T₃ increases levels of both the hepatic LDL receptor [9] andits mRNA [10]. Additional thyroid hormone actions on lipid metabolisminclude increasing the activity of lipoprotein lipase [11].

Numerous studies have been carried out to synthesize thyroid hormoneanalogs that mimic the actions of the natural hormones. The objective ofmost of these efforts has been to develop thyromimetics that lowerplasma cholesterol without adverse cardiac effects. A series ofthyroxine analogs and methods of synthesis are described in U.S. Pat.No. 3,109,023. Thyroid hormone agonists that are highly selective forthe thyroid hormone receptor (TR) β-subtype are described in U.S. Pat.No. 5,883,294 and WO 00/39077. U.S. Pat. No. 5,284,971 describes a classof thyromimetics, which have the distinguishing characteristic of asulfonyl bridge in the diphenyl core.

The usual method employed in treating obesity has been reduction ofcaloric intake either by reduced caloric diet or appetite suppression.An alternative method is to stimulate metabolic rate in adipose tissue.For example U.S. Pat. Nos. 4,451,465, 4,772,631, 4,977,148 and 4,999,377disclose compounds possessing thermogenic properties at dosages causingfew or no deleterious side-effects, such as cardiac stimulation. Furtherpharmaceutical compositions including those selective for the β-typethyroid hormone receptor have been taught by Cornelius et al. in US2002/0035153 A1. A representative compound of this type,N-[4-[3′[(4-fluorophenyl)hydroxymethyl]-4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamate(CGS-26214) reportedly is devoid of significant cardiovascular effectsbut possess significant thermogenic properties. Accordingly, CGS-26214and related compounds are useful in the treatment of obesity and relatedconditions in humans and companion animals. According to Cornelius etal. compounds related to CGS-26214 may be combined with an anorecticagent such as phenylpropanolamine, ephedrine, pseudoephedrine,phentermine, a Neuropeptide Y antagonist, a cholecystokinin-A agonist,etc. Whereas administration of a selective β-agonist would compensatefor endogenous hormones in terms of TRβ stimulation it may notsignificantly activate TRα, which could cause a relative hypothyroidismor could cause increased hepatic toxicity. Also, there is no informationon whether weight loss would be selective for fat or would includemuscle as well.

Goglia and Lanni in WO2005009433 describe the use of a breakdown productof thyroid hormone (3,5-diiodothyronine) as a regulator of lipidmetabolism to stimulate burning of fatty acid in mitochondria. T₃, whichis largely derived from T₄ by the action of monodeiodinases, has beenthought to be the major active form of thyroid hormone. It has beenreported that 3,5-diiodothyronine (3,5-T₂) is able to directly increasemitochondrial respiration by increasing the burning of fatty acids. Inkeeping with the stimulation of mitochondrial respiration, fatty acidoxidation rate was increased by 3,5-T₂. In rats fed a high-fat dietlong-term treatment with 3,5-T₂ reportedly decreased weight gain. Theseeffects were observed without suppression of TSH or evidence ofhyperthyroidism. 3,5-T₂ also was given to four volunteers in daily dosesbetween 15 and 90 microgram/kg. There was a reduction in plasma levelsof triglycerides from 140-70 mg/dL and cholesterol from 241 mg/dL to 210mg/dL. The resulting metabolic rate increased in a dose dependent mannerreaching a maximum increase of 40% (from 1770 Kcal to 2400 Kcal perday). Fat mass was reduced in the range of 10 to 15%. There was nosignificant change in plasma levels of free T₃ and free T₄.

The actions of 3,5-T₂ and T₃ on mitochondrial respiration can bedistinguished by differences in the time course of the response [12].Changes in resting metabolic rate in hypothyroid rats treated with asingle injection of 3,5-T₂ started 6-12 hours after infection with themaximal stimulation at 28-30 hours. By contrast injection of T₃increased resting metabolic rate that started 25-30 hours afterinjection and lasted 5-6 days. At the mitochondrial level stimulation isvery rapid after injection of 3,5-T₂, occurring within 1 hour.

In my parent application, now U.S. Pat. No. 6,534,676, I describe andclaim the use of a thyroid hormone analog 3,5-diiodothyropropionic acid(DITPA) for treating patients with congestive heart failure. Moreparticularly, as reported in my aforesaid U.S. Pat. No. 6,534,676, DITPAhas been shown to improve left ventricular (LV) performance inpost-infarction experimental models of heart failure when administeredalone or in combination with an angiotension I-converting enzymeinhibitor. Cholesterol was significantly reduced in heart failurepatients receiving DITPA after two and four weeks treatment, P<0.05 andP<0.1, respectively. In addition, it was noted that triglycerides weresignificantly reduced in these heart failure patients at two and fourweeks of treatment with P<0.05 and P<0.005, respectively.

3,5-T₂ and DITPA differ only in the side chain attached to the innerphenolic ring. In each case, the side chain consists of 3 carbons,ending in an amino acid group in 3,5-T₂ and a carboxylic acid in DITPA.The structural similarity suggests the compounds should have somephysiologic similarities. As reported in my aforesaid U.S. Pat. No.6,534,676 normal volunteers and patients with heart failure indicate twosuch similarities: 1) There was significant weight loss in heart failurepatients, who were obese and poorly conditioned, but no significant lossin volunteers who were more active and free of significant heartdisease; and 2) Unexpectedly, there was a decrease not only in totalcholesterol and LDL-cholesterol but also a highly significant decreasein triglycerides (P=0.005). A decrease in triglycerides also was seenwith administration of 3,5-T₂, but to my knowledge, has not previouslybeen reported either with thyroid replacement in hypothyroidism or inthe case of thyroid hormone analogs [13].

SUMMARY OF THE INVENTION

The new and surprising effect I have found is that administration of3,5-diiodothyropropionic acid (DITPA) not only reduces total cholesteroland low-density lipoprotein (LDL) cholesterol when it is administered tooverweight euthyroid individuals, it stimulates weight loss, and alsoreduces triglycerides, particularly in overweight individuals.

Adipose tissue is the largest storehouse of energy in the body (in theform of triglycerides) and typically makes up 15-20% or more of the bodyweight in men and 20-25% or more of the body weight in women. Thyroidhormones exert a wide range of effects on lipid metabolism. In thethyrotoxic state lipid mobilization, synthesis and degradation are allaccelerated. Degradation of most lipids is stimulated out of proportionto synthesis and as a consequence body lipid deposits are depleted.Thus, administration of DITPA is seen to stimulate weight loss and lowerhypertriglyceridemia, particularly in overweight patients, and may beused to treat or to reduce risk of death or progression of coronaryheart disease (CHD) in patients with metabolic syndrome.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

DITPA was synthesized following good manufacturing procedures bycoupling dianisoleiodium trifluoroacetate withethyl-3-(3,5-diiodo-4-hydroxyphenyl)-propionate followed by removal ofthe methyl and ethyl protective groups as described in my aforesaid U.S.Pat. No. 6,534,676.

The effects of administering DITPA were studied in 7 volunteers all butone of whom had normal weight. Study participants were men between theages of 27 and 52 years. Of note, there was an average weight loss ofonly 0.6 kg for the group, or 0.7% of their initial weight, which didnot attain statistical significant (P=0.13). Body Mass Index (BMI) wascalculated as a meaning of judging obesity. BMI is a measure of body fatbased on height and weight that applies to both men and women. Excludingthe one overweight individual BMI ranged from 21.0 to 26.7 (average25.0). (The range of normal weight for men is 20.7 to 26.4, marginallyover weight 26.4 to 27.8, overweight 27.8 to 31.1, and very obese isgreater than 31.1). BMI was calculated using the BMI calculator at theNational Heart, Lung, and Blood Institute web site(nhlbisupport/com/bmi/). BMI and lipid data for the six volunteers ofnormal body weight are summarized in Table I A&B:

TABLE I (a) Healthy Volunteers Treated with DITPA BMI Initials (kg/m²)T. M. 24.4 T. V. 24.4 K. L. 27.4 A. M. 26.7 J. B. 21.0 R. F. 26.1 Mean25.0 SE 0.9

TABLE 1 (b) Healthy Volunteers Treated with DITPA Cholesterol LDL-CHDL-C Triglycerides Initials mg/dL mg/dL mg/dL mg/dL Baseline: TM 190112.6 53 122 TV 181 119.6 25 182 KL 320 538 AM 191 160.4 9 108 JB 13375.4 41 83 RF 198 139.8 37 106 Mean 202.2 121.6 33.7 189.8 SE 25.4 14.27.5 71.0 After 2 weeks: TM 191 120.6 50 102 TV 141 86.8 31 116 KL 298142.6 36 597 AM 164 102.2 28 169 JB 94 47.4 30 83 RF 149 90.2 38 104Mean 172.8 98.3 35.5 195.2 SE 28.2 12.3 3.3 81.2 After 4 weeks: TM 187109.4 52 128 TV 122 71 27 120 KL 305 137 31 685 AM 168 106 JB 79 68 RF182 118.2 45 94 Mean 173.8 108.9 38.8 200.2 SE 31.2 13.9 5.9 97.4

Cholesterol levels ranged from 133 mg/dL to 320 mg/dL (average202.2±25.4 mg/dL), LDL-cholesterol 121.6±14.2, HDL-cholesterol 33.7±7.5.Triglycerides levels ranged from 83 mg/dL to 538 mg/dL (average189.8±71.1 mg/dL) before treatment. On day 1, these normal volunteerswere started on 1.875 mg/kg DITPA in two divided doses per day. Thistreatment regimen was continued for two weeks. At the end of the secondweek, the dose was doubled to 3.75 mg/kg and the volunteers were treatedfor two additional weeks.

After two weeks of treatment with DITPA cholesterol levels weredecreased to an average of 172.8±28.2 mg/dL, LDL-cholesterol to98.3±13.3 mg/dL. HDL-cholesterol and triglycerides were unchanged at35.5±3.3 mg/dL and 195.2±81.2 mg/dL, respectively. After four weeks oftreatment cholesterol, LDL-cholesterol, HDL-cholesterol and triglyceridelevels were essentially unchanged from values after 2 weeks oftreatment. Note that triglyceride levels in the one individual (K. L.)with very high triglyceride levels, was unaffected by treatment. Thustreatment with DITPA in individuals of normal body weight loweredcholesterol and LDL-cholesterol but did not cause weight loss or adecrease in triglycerides.

Treatment was repeated with a second group of 8 patients with heartfailure. (One patient with heart failure treated with DITPA reported inU.S. Pat. No. 6,716,877 was excluded because no lipid data wereavailable at baseline.) Those in the second group had Body Mass Indicesranging from 21.0 to 30.3 (average 32.2, which was in the obese range).The patients in this group received an initial dose of 1.875 mg/kg fortwo weeks, which was doubled to 3.75 mg/kg for two additional weeks. Asreported earlier, heart failure patients receiving DITPA experienced anaverage weight loss of 4 kg or 4.0% of their initial body weight(P=0.059).

TABLE II (a) Heart Failure Patients Treated with DITPA BMI Initials(kg/m²) R. V. 45.5 J. G. 36.2 F. R. 28.1 E. C. 30.2 J. D. 30.0 J. F.31.3 W. P. 36.9 C. H. 23.9 Mean 31.5 SE 2.4

TABLE II (b) Heart Failure Patients Treated with DITPA Cholesterol LDL-CHDL-C Triglycerides Initials mg/dL mg/dL mg/dL mg/dL Baseline: R. V. 195141 27 133 J. G. 217 104 23 449 F. R. 102 48 30 119 E. C. 144 62 38 219J. D. 186 94 28 321 J. F. 241 167 48 128 W. P. 168 89 31 238 C. H. 233152 37 222 Mean 185.8 107.1 32.8 228.6 SE 16.6 15.1 2.8 39.8 After 2weeks: R. V. 161 107 30 120 J. G. 150 88 20 208 F. R. 106 55 27 119 E.C. 128 50 32 228 J. D. 176 88 28 300 J. F. 244 177 41 131 W. P. 177 8134 312 C. H. 190 99 28 317 Mean 166.5 93.1 30.0 216.9 SE 14.8 13.9 2.130.6 After 4 weeks: R. V. 143 102 26 77 J. G. 125 69 20 179 F. R. 83 4326 69 E. C. 107 41 31 176 J. D. 144 77 26 205 J. F. 243 172 52 93 W. P.127 68 32 135 C. H. 189 102 36 253 Mean 145.1 84.3 31.1 148.4 SE 17.714.9 3.4 23.3

At baseline average cholesterol values were 185.8±16.6 mg/dL,LDL-cholesterol 107.1±15.1 mg/dL, HDL-cholesterol 32.8±2.8 mg/dL andtriglycerides 228.6±39.8 mg/dL. After two weeks of treatment with DITPAcholesterol decreased to 166.5±14.8 mg/dL, LDL-cholesterol to 93.1±13.9mg/dL and triglycerides to 216.9±30.6 mg/dL. After four weeks oftreatment cholesterol decreased to 145.1±17.7, LDL-cholesterol to84.3±14.9 and triglycerides to 148.4±23.3. The decrease in triglyceridesof 35% is comparable to that reported by Goglia and Lanni in normalvolunteers treated with 3,5-T₂. Of particular interest, the two patients(J. G. and J. D.), with triglycerides of greater than 300, had decreasesin triglycerides of 60% and 36%, respectively.

It is thus seen that administration of DITPA caused a greater decreasein weight of overweight individuals than those of normal body weight.Triglycerides also were decreased to a greater extent in overweightindividuals. In these individuals, the triglycerides were decreased bothin those with normal and elevated triglycerides levels.

As used herein, the terms “overweight individuals” and “overweightpatients” are those individuals or patients having a Body Mass Index of30 or more.

As used herein, “therapeutically effective amounts” or “effective doselevels” for achieving weight loss and lowering of triglyceride levels ofoverweight individuals were 0.1 to 10.0 mg/kg daily, preferably 1.875 to3.75 mg/kg daily. Preferably, the daily doses were divided in half andadministered twice daily.

While the invention has been described in detail in treating humans inaccordance with certain preferred embodiments the invention alsoadvantageously may be used for treating overweight animals such as dogsand cats, and other domesticated animals. Also, while administration ofDITPA appears to reduce triglycerides, particularly in overweightindividuals, individuals of normal weight also may benefit by areduction of triglycerides from administration of DITPA in accordancewith the present invention. Moreover, DITPA advantageously may becombined with one of the conventional lipid/triglyceride loweringtherapeutic agents such as HMG CoA reductase inhibitors commonlyreferred to as ‘statins’, e.g., atorvastatin (Lipitor), simvastatin(Zocor), fluvastatin (Lescol), lovastatin (Mevacor), rosuvastatin(Crestor), and pravastatin (Pravachol) or the like. Niacin andinhibitors of cholesterol absorption such as ezetimibe (Zetia) also maybe combined with DITPA. For treatment of hypertriglyceridemia fibricacid derivative such as gemfibrozil (Lopid), fenofibrate (Tricor), etc.may be combined with DITPA. Still other modifications and changestherein may be made without departing from the spirit and scope of theinvention.

REFERENCES

-   1. Ford ES, Giles WD, Dietz WH: Prevalence of the metabolic syndrome    among US adults. Findings from the third national health and    nutrition examination survey. JAMA 287:356-359,2002-   2. Mason RL, Hunt HM, Hurxthal LM: Blood cholesterol values in    hyperthyroidism and hypothyroidism: their significance. N Eng J Med    203:1273-1278, 1930-   3. Peters JP, Man EB: The significance of serum cholesterol in    thyroid disease. J Clin Invest 29:1-11, 1950-   4. Ladenson PW, Goldenheim PD, Ridgway EC: Rapid pituitary and    peripheral tissue responses to intravenous L-triiodothyronine in    hypothyroidism. J Clin Endocrinol Metab 56:1252-1259, 1983.-   5. The Thyroid. A Fundamental and Clinical Text. 6th Ed., Editors:    L.E. Braverman and R.D. Utiger, J.B. Lippincott Co., pp. 489-490.-   6. Walton KW, Campbell DA, Tonks EL: The significance of alterations    in serum lipids in thyroid dysfunction. I. The relation between    serum lipoprotein, carotenoids and vitamin A in hypothyroidism and    thyrotoxicosis. Clin Sci 29:199-215, 1965.-   7. Walton KW, Scott PJ, Dykes PW, Davies JW: The significance of    alternations in serum lipids in thyroid dysfunction. II. Alterations    of metabolism and turnover of 131-I-low-density lipoproteins in    hypothyroidism and thyrotoxicosis. Clin Sci 29:217-238-   8. Abrams JJ, Grundy SM: Cholesterol metabolism in hypothyroidism    and hyperthyroidism in man. J Lipid Res 22:323-338, 1981.-   9. Staels B. Van Tol A, Chan L, Will HM, Verhoeven GA, Auwerx J:    Alterations in thyroid status modulate apolipoprotein, hepatic    triglyceride lipase, and low-density lipoprotein receptor in rats.    Endocrinology 127:1145-1152.-   10. Salter AM, Hayashi R, Al-Seeni M, Brown NF, Bruce J, Sorensen O,    et al.: Effects of hypothyroidism and high-fat feeding on mRNA    concentrations for the low-density lipoprotein receptor and on    acyl-CoA:cholesterol acyltransferase activities in rat liver.    Biochem J 276:825-832, 1991.-   11. Packer CJ, Shepard J, Lindsay GM, Gaw A, Taskinen MR: Thyroid    replacement therapy and its influence on postheparin plasma lipases    and apolipoprotein-β metabolism in hypothyroidism. J Clin Endocrinol    Metab 76:1209-1216, 1993.-   12. Moreno M, Lanni A., Lombardi A, Goglia F: How the thyroid    controls metabolism in the rat: different roles for triiodothyronine    and diiodothyronines. J Physiol (London) 505:529-538, 1997.-   13. Morkin E, Ladenson P, Goldman S, Adamson C: Thyroid hormone    analogs for treatment of hypercholesterolemia and heart failure:    past, present and future prospects. J Mol Cell Cardiol 37:1137-1146,    2004.

1-29. (canceled)
 30. A method of reducing risk of death or progressionof coronary heart disease in patients with metabolic syndrome comprisingadministering to the patient a therapeutically effective amount of3,5-diiodothyropropionic acid.
 31. The method of claim 30, wherein3,5-diiodothyropropionic acid is administered as a formulation selectedfrom the group consisting of a liquid preparation, a solid preparation,a capsule preparation, and an implant preparation.
 32. The method ofclaim 31, wherein said formulation further comprises a pharmaceuticallyacceptable carrier.
 33. The method of claim 32, wherein said formulationfurther comprises at least one of a stabilizer, an excipient, asolubilizer, an antioxidant, a pain-alleviating agent, and an isotonicagent.
 34. The method of claim 30, wherein said 3,5-diiodothyropropionicacid is administered by parenteral injection.
 35. The method of claim34, wherein said 3,5-diiodothyropropionic acid is administered byparenteral intravenous injection.
 36. The method of claim 30, whereinsaid 3,5-diiodothyropropionic acid is administered orally.
 37. Themethod of claim 30, wherein said 3,5-diiodothyropropionic acid isadministered directly to the pulmonary system of the patient.
 38. Themethod of claim 30, wherein said 3,5-diiodothyropropionic acid isadministered transdermally.
 39. The method of claim 30, wherein said3,5-diiodothyropropionic acid is administered by implantation.
 40. Themethod of claim 30, wherein said 3,5-diiodothyropropionic acid isadministered at a daily dosage of 0.1 to 10.0 mg/kg.
 41. The method ofclaim 40, wherein said daily dosage is from 1.875 to 3.75 mg/kg.
 42. Themethod of claim 30, wherein said 3,5-diiodothyropropionic acid isadministered with a conventional lipid/triglyceride lowering therapeuticagent.
 43. A method of treating patients with metabolic syndromecomprising administering to the patient a therapeutically effectiveamount of 3,5-diiodothyropropionic acid.
 44. The method of claim 43,wherein 3,5-diiodothyropropionic acid is administered as a formulationselected from the group consisting of a liquid preparation, a solidpreparation, a capsule preparation, and an implant preparation.
 45. Themethod of claim 44, wherein said formulation further comprises apharmaceutically acceptable carrier.
 46. The method of claim 43, whereinsaid formulation further comprises at least one of a stabilizer, anexcipient, a solubilizer, an antioxidant, a pain-alleviating agent, andan isotonic agent.
 47. The method of claim 43, wherein said3,5-diiodothyropropionic acid is administered by parenteral injection.48. The method of claim 47, wherein said 3,5-diiodothyropropionic acidis administered by parenteral intravenous injection.
 49. The method ofclaim 43, wherein said 3,5-diiodothyropropionic acid is administeredorally.
 50. The method of claim 43, wherein said3,5-diiodothyropropionic acid is administered directly to the pulmonarysystem of the patient.
 51. The method of claim 43, wherein said3,5-diiodothyropropionic acid is administered transdermally.
 52. Themethod of claim 43, wherein said 3,5-diiodothyropropionic acid isadministered by implantation.
 53. The method of claim 43, wherein said3,5-diiodothyropropionic acid is administered at a daily dosage of 0.1to 10.0 mg/kg.
 54. The method of claim 53, wherein said daily dosage isfrom 1.875 to 3.75 mg/kg.
 55. The method of claim 43, wherein said3,5-diiodothyropropionic acid is administered with a conventionallipid/triglyceride lowering therapeutic agent.